The increasing incidence of obesity is a major health issue facing the USA. Moreover, the mechanisms underlying anorexia nervosa remain poorly understood. Fortunately, in the past decade several key hormones and CNS pathways controlling body weight have been identified. Indeed, we now have a rough CNS roadmap through which key metabolic signals like leptin exert its effects which may lead to effective strategies to combat the incidence of obesity and eating disorders. In the past award period we sought to delineate the neural substrates through which 5-HT compounds selectively regulate food intake and body weight. We focused on the potential interactions of leptin-regulated neuronal systems and CNS serotonin (5-HT) systems. We found that 5-HT and leptin both converge on hypothalamic melanocortin neurons. Collectively, our data suggests that the central melanocortin system is one of the downstream mediators of the ability of 5-HT to regulate body weight and glucose homeostasis. In the current proposal we will extend these observations using a mouse model in which we can selectively reactivate melanocortin 4 receptor (MC4-R) expression. We will identify CNS sites expressing MC4-Rs that are sufficient for 5-HT to regulate body weight and glucose homeostasis. Our recent findings also suggest that leptin action on extrahypothalamic neurons is physiologically important. However, very little is known about the chemical identity of extra-hypothalamic leptin-responsive neurons. In the current application, we seek to determine the chemical identity and physiological significance of several extra-hypothalamic cell groups expressing leptin receptors. To accomplish this, we will use unique mouse models to identify the chemical identities and CNS sites targeted by leptin-responsive neurons. We will also use novel models in which we can selectively reactivate leptin receptor (ObRb) expression in specific CNS sites to allow us to assess the physiological relevance of leptin receptor expression in the midbrain and brainstem.